EP1349562A2 - Inhibiting gs-fdh to modulate no bioactivity - Google Patents
Inhibiting gs-fdh to modulate no bioactivityInfo
- Publication number
- EP1349562A2 EP1349562A2 EP01987141A EP01987141A EP1349562A2 EP 1349562 A2 EP1349562 A2 EP 1349562A2 EP 01987141 A EP01987141 A EP 01987141A EP 01987141 A EP01987141 A EP 01987141A EP 1349562 A2 EP1349562 A2 EP 1349562A2
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- Prior art keywords
- patient
- glutathione
- ceus
- proliferating
- effective amount
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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- A61P11/00—Drugs for disorders of the respiratory system
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- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the invention relates to modulating NO (nitric oxide) bioactivity to obtain therapeutic effect.
- Stamler et al. U.S. Patent No. 6,057,367 is directed to treating mammals for infections or for conditions associated with pathologically proliferating mammalian cell growth (for example, certain cancers, restenosis, benign prostatic hypertrophy) by administration of a manipulator of mtrosative stress (an impetus for NO or NO 2 group attachment to proteins, nucleic acids or other biological molecules) to selectively kill or reduce the growth of the microbes or hehr ⁇ iths causing the infection or of host cells infected with the microbes or of the pathologically proliferating mammalian cells.
- a manipulator of mtrosative stress an impetus for NO or NO 2 group attachment to proteins, nucleic acids or other biological molecules
- Stamler et al. U.S. Application No. 09/695,934 discloses use of NO donors to prevent the occurrence of restenosis following angioplasty, to inhibit platelets to prevent coagulation and thrombus formation, to treat angina in patients at risk for coagulation and thrombus formation, to inhibit microbes, to treat impotence, asthma, cystic fibrosis, hypoxia and ischemic disorders, heart failure, stroke, arthritis, ARDS, hypertension, neurodegeneration, painfiil crisis of sickle cell disease, cancer and any pathological proliferation of cells and any NMDA related injury.
- the invention is directed to C-nitroso compounds and use thereof as NO donors.
- Gaston, Stamler and Griffith U.S. Application No. 08/403,775 is directed to use of inhibitors of S-nitrosothiol breakdown to treat asthma.
- alcohol dehydrogenases including alcohol dehydrogenase Class IH (also known as glutathione-dependent formaldehyde dehydrogenase), see the following publications which present in vitro data: Kuwada, M., et al. J. Biochem. 88, 859-869 (1980); Jensen, D. E., et al., Biochemical Pharmacology 53, 1297-1306 (1997); Jensen, D. E., et al., Biochem. J. 331, 659-668 (1998).
- Alcohol dehydrogenase Class IH also known as glutathione-dependent formaldehyde dehydrogenase
- enzyme namely glutathione-dependent formaldehyde dehydrogenase known heretofore to oxidize the formaldehyde glutathione adduct, S-hydroxymethylglutathione, previously thought to be the major enzyme substrate, functions in vivo to metabolize S-nitrosoglutathione and protein S-nitrosothiols to modulate NO bioactivity, by controlling the intraceUular levels of low mass NO donor compounds and preventing protein nitrosylation -from reaching toxic levels.
- enzyme namely glutathione-dependent formaldehyde dehydrogenase known heretofore to oxidize the formaldehyde glutathione adduct, S-hydroxymethylglutathione, previously thought to be the major enzyme substrate, functions in vivo to metabolize S-nitrosoglutathione and protein S-nitrosothiols to modulate NO bioactivity, by controlling the intraceUular levels of low mass NO donor compounds and preventing protein nitrosylation -from
- One embodiment herein is directed to a method of treating a patient afflicted with a disorder ameliorated by NO donor therapy, said method comprising administering to said patient a therapeutically effective amount of an inhibitor of glutathione-dependent formaldehyde dehydrogenase.
- Another embodiment herein is directed to a method for treating a patient afflicted with pathologically proliferating cells, said method comprising administering to said patient a therapeutically effective amount of an inhibitor of glutathione-dependent formaldehyde dehydrogenase.
- pathologically proliferating cells is used herein to include pathologic microbes, pathologic helminths, and pathologically proliferating m--u-- ⁇ maha- ⁇ cells.
- Still another embodiment herein is directed to increasing NO bioactivity for pharmacological effect or in the case of diseases associated with a deficiency of NO.
- This embodiment is directed to a method of treating a patient in need of increased nitric oxide bioactivity, said method comprising administering to said patient a therapeutically effective amount of glutathione-dependent formaldehyde dehydrogenase.
- Glutathione-dependent formaldehyde dehydrogenase is a known enzyme which is conserved from microbes including bacteria and fungi to mammals. It is also known as alcohol dehydrogenase Class HL It has been identified in a variety of bacteria, yeasts, plants and animals. The proteins fiomE. coli, S. cerevisiae and mouse macrophages share over 60% arr ⁇ io acid sequence identity. Li methylotropic microorganisms, GS-FDH is induced by methanol to prevent formaldehyde accumulation. The physiological significance of formaldehyde oxidation by GS-FDH is less clear in other microorganisms and animals.
- GS-FDH associated NADH- ependent S-nitrosoglutathione reductase activity has been detected in E. coli, in mouse macrophages, in mouse endotheUal ceUs, in mouse smooth muscle ceUs, in yeasts, and in human HeLa, epitheUal and monocyte ceUs.
- glutathione-dependent formaldehyde dehydrogenase means enzyme that oxidizes S- hydroxymethylglutathione and also provides NADH-dependent S-nitrosoglutathione reductase activity (i.e., decomposes S-nitrosoglutathione when NADH is present as a required cofactor) and shares at least 60% amino acid sequence identity with enzymes having the same function fiomE. coli, S. cerevisiae and mouse macrophages.
- the glutathione-dependent formaldehyde dehydrogenase may also be referred to as S-nitrosoglutathione reductase.
- One class of compounds for use herein as the inhibitors of glutathione-dependent formaldehyde dehydrogenase is constituted of competitors for NAD + binding. These -i- ⁇ Mbitors work by binding to the NAD + cofactor binding site of the enzyme and thereby block the NADH cofactor from binding to the enzyme.
- NR liicotinamide riboside
- This compound requires additionaUy metaboUzation to 6-amino-NAD(P + ) by the pentose phosphate pathway (PPP) enzyme, 6-phosphogluconate dehydrogenase, for inhibitory activity.
- PPP pentose phosphate pathway
- tiazofurin is phosphorylated by adenosine kinase to the 5 -monophosphate and converted by NAD- pyrophosphorylate to TAD, described later, for competitive binding.
- BR benzamide ribosome
- BR is metabolized to (BAD), described later, for activity.
- StiU another ribonucleoside analog which is a competitor for NAD + binding and thereby inhibits the S-nitrosoglutathione reductase activity of GS-FDH is ribavirin which has the formula:
- MZR mizoribine
- EICAR 5- ethynyl-l- ⁇ -D-ribofi ⁇ ranosyli--mdazole-4-carboxamide
- NAD + Another compound which is an inhibitor of GS-FDH by virtue of being a competitor for NAD + binding is NAD + which has the formula:
- NAD + derivative 6-amko-NAD which has the formula:
- C-NAD 5- ⁇ -D-riboft ⁇ ranosy---ucotinamide adenine dinucleotide
- This compound is a metaboUte of Compound (3) described above.
- C-PAD 6- ⁇ -D-ribofiu-anosylpicolinamide adenine dinucleotide
- the derivatives of formulas (18) and (19) including Compounds (18a), (18b), (18c), (18d), (18e), (18f), (19a) and (19b) are TAD (Compound (15c)) and BAD (Compound (16)) analogs which are metaboUcaUy stable and ceU membrane permeable, methylene or difluoromethylene bis (phosphonate)s, and analogs substituted with fluorine in the ribose moiety of adenosine which are more hydrophobic than their hydroxy congeners.
- Compound (20) has the formula:
- Compound (21) has the fo ⁇ nula:
- StiU other compounds which are inhibitors of GS-FDH are competitive substrates for NADH binding. These include 6-thioanologs of natural purine bases, e.g., 6- mercaptopurine (Compound 22) and 6-thioguanine (Compound 23).
- Compound (22) has the formula:
- Compound (23) has the formula:
- the above Compounds (1) - (23) are considered also to inhibit the activity of other NADH dependent dehydrogenases such as inosine monophosphate dehydrogenase (HVEPDH).
- HVEPDH inosine monophosphate dehydrogenase
- Other inhibitors of IMPDH by virtue of competition for NAD + cofactor binding site, are also effective as inhibitors of GS-FDH herein.
- the compounds specificaUy described above are avaUable commerciaUy or their synthesis is described in or obvious from the Uterature.
- tiazofurin has been used previously for antineoplastic activity against tumors as has t ophenfurin and selenazofurin.
- selenazofurin, ribavirin, MZR, EICAR and MMF have been used for antiviral or potential antiviral activity.
- mycophenoUc acid has been evaluated as an anticancer, antiviral, antifiuigal and antibacterial agent, as weU as for its therapeutic use in psoriasis and rheumatoid arthritis.
- ftiranfurin and ribavirin have been shown to be inactive as an antitumor agents.
- Another class of compounds useful herein to inhibit GS-FDH is constituted of glutathione derivatives including D-glutathione and S-alkyl glutathione containing from 1 to 6 carbon atoms in the S-alkyl group.
- the disorders appUcable to this embodiment include, for example, breathing disorders (e.g., asthma, cystic fibrosis, and ARDS), heart disease, hypertension, ischemic coronary syndromes, atherosclerosis, glaucoma, diseases characterized by angiogenesis (e.g., coronary artery disease), disorders where there is risk of thrombosis occurring, disorders where there is risk of restenosis occurring, chronic inflammatory diseases (e.g., ADD dementia and psoriasis), diseases where there is risk of apoptosis occurring (e.g., heart faUure, atherosclerosis, degenerative neurologic disorders, arthritis and liver injury (ischemic or alcohofic)), impotence, obesity caused by eating in response to craving for food, stroke, reperfusion injury (e.g., traumatic muscle injury in heart or lung or crush injury), and disorders where preconditioning of heart or brain for NO protection against subsequent ischemic events is beneficial.
- breathing disorders e.g., asthma, cystic
- therapeutically effective amount for this first embodiment means a glutathione-dependent formaldehyde dehydrogenase inhibiting amount in vivo that causes ameUoration of the disorder being treated or protects against a risk associated with the disorder.
- a therapeuticaUy effective amount is a bronchodilating effective amount; for cystic fibrosis, a therapeuticaUy effective amount is an airway obstruction ameUorating effective amount; for ARDS, a therapeuticaUy effective amount is a hypoxemia ameUorating effective amount; for heart disease, a therapeuticaUy effective amount is an angina reUeving or angiogenesis inducing effective amount; for hypertension, a therapeuticaUy effective amount is a blood pressure reducing effective amount; for ischemic coronary disorders, a therapeutic amount is a blood flow increasing effective amount; for atherosclerosis, a therapeuticaUy effective amount is an endotheUal dysfunction reversing effective amount; for glaucoma, a therapeutic amount is an intraocular pressure reducing effective amount; for diseases characterized by angiogenesis, a therapeuticaUy effective amount is an angiogenesis inhibiting effective amount; for disorders where there is risk of thrombosis occurring, a therapeuticaUy effective amount
- the dosage i.e, the therapeuticaUy effective amount
- the patients include mammals including humans.
- the preferred route of administration is oral administration although other routes of administration including parenteral are useful. Topical administration can be appropriate for localized disorders.
- Preferred treating agents for the first embodiment include D-glutathione, ribavirin, D-glutathione together with ribavirin, and mycophenoUc acid.
- D-Glutathione can be given, for example, intravenously at 10-100 mg/kg and/or inhaled in 1-10 mM concentration for asthma; inhaled at 1-10 mM concentration for cystic fibrosis and ARDS; and intravenously at 10-300 mg/kg for heart disease including angina, ischemic coronary syndrome, and disease where there is risk of apoptosis occurring (e.g., acetaminophen induced liver injury), and at 100 to 1,000 mg for hypertension.
- apoptosis e.g., acetaminophen induced liver injury
- Ribavirin can be given, for example, injected in an amount of 1-10 g at a concentration of 5-25 mg/ml for angina from coronary artery disease, inhaled in amount of 1 to 10 grams to prevent thrombosis from occurring, e.g., where pulmonary emboUsm is found, and topicaUy at 1-5% in a topical composition for psoriasis.
- MycophenoUc acid can be given, for example, coated on a stent (drug concentration 10-40% per polymer) for treating restenosis or topicaUy at a concentration of 1 to 10% in a paste to treat impotence.
- Treatment is continued as long as symptoms and/or pathology ameUorate.
- pathologicaUy proliferating ceUs are pathologicaUy proliferating microbes.
- the microbes involved are those where glutathione-dependent formaldehyde dehydrogenase is expressed to protect the microbe from nitrosative stress or where host ceU infected with said microbe expresses said enzyme thereby protecting the microbe from nitrosative stress.
- pathologicaUy proliferating microbes is used herein to mean pathologic microorganisms including but not limited to pathologic bacteria, pathologic viruses, pathologic Chlarnydia, pathologic protozoa, pathologic Rickettsia, pathologic fungi, and pathologic mycoplasmata. More detaU on the appUcable microbes is set forth at columns 11 and 12 of U.S. Patent No. 6,057,367 which are incorporated here by reference.
- host ceUs infected with pathologic microbes includes not only mammaUan ceUs infected with pathologic viruses but also rnammaUan ceUs containing intraceUular bacteria or protozoa, e.g., macrophages containing Mycobacterium tuberculosis, Mycobacterium leper (leprosy), or Salmonella typhi (typhoid fever).
- pathologicaUy proliferating ceUs are pathologic helminths.
- pathologic helminths is used herein to refer to pathologic nematodes, pathologic trematodes and pathologic cestodes. More detaU on the appUcable helminths is set forth at column 12 of U.S. Patent No. 6,057,367 which is incorporated herein by reference.
- pathologicaUy proliferating mammaUan ceUs means ceUs of the mammal that grow in size or number in said mammal so as to cause a deleterious effect in the mammal or its organs.
- the term includes, for example, pathologicaUy proliferating cancer cells, the pathologicaUy proliferating or enlarging ceUs causing restenosis, the pathologicaUy proliferating or enlarging ceUs causing benign prostatic hypertrophy, the pathologicaUy proliferating ceUs causing myocardial hypertrophy and proliferating ceUs at inflammatory sites such as synovial ceUs in arthritis.
- PathologicaUy proliferating cance-f cells include the ceU proliferation in Hodgkin's disease, in small ceU lung cancer, in cancer of the breast, and in testicular and prostate cancer.
- the inhibitors of glutathione-dependent formaldehyde dehydrogenase for this second embodiment herein are those described above.
- the thera euticaUy effective amount for this second embodiment means a glutathione-dependent formaldehyde dehydrogenase inhibiting amount in vivo which is an antiproUferative effective amount.
- antiproUferative effective amount as used herein means an amount causing reduction in rate of proliferation of at lest 10%.
- the dosage i.e., the therapeuticaUy effective or antiproUferative effective amount
- the dosage ranges from 1 ⁇ g to 10 g/kg and often ranges from 10 ⁇ g to 1 g/kg or 10 ⁇ g to 100 mg/kg body weight of the patient being treated, per day.
- the patients are mammals including humans.
- the preferred route of administration in respect to inhibiting growth of microbes is oral administration although other routes of administration including parenteral and topical are useful.
- Topical administration is especiaUy useful for exposed infections, e.g., fungal infections such as athlete's foot, viral infections such as herpes and microbe-caused oral or skin lesions.
- the prefened route of administration is oral administration although other routes of administration including parenteral are useful.
- the route of administration can be oral or parenteral and local administration is possible, for example, by infusion directly into a tumor or into the blood vessels delivering blood to the tumor, or by forming the agent into a slow release peUet or into a polymer matrix and then implanting the peUet or polymer matrix device in or on the tumor.
- the preferred routes of administration in the case of inhibiting growth of pathologicaUy proliferating mammaUan ceUs that would cause restenosis is from attachment on a stent implanted in angioplasty but systemic including oral and intravenous administration can be acceptable.
- the prefened route of administration in the case of inhibiting growth of pathologicaUy proliferating mammaUan ceUs causing benign prostatic hypertrophy is from attachment on a prostatic implant or by local injection.
- pathologicaUy proliferating ceUs comprise pathologic bacteria or fungus and the patient is afflicted with a bacterial or fungal infection
- the pathologicaUy proliferating ceUs are pathologicaUy proliferating mammaUan ceUs
- Preferred treating agents for the second embodiment include D-glutathione, ribavirin, D-glutathione together with ribavirin, and mycophenoUc acid.
- D-Glutathione can be given, for example, inhaled at 1-10 mM concentration for viral pneumonia; oraUy at a dose of 0.2 to 2 grams daUy for pinworm and Hodgkin's disease, to inhibit restenosis after angioplasty and to resolve benign prostatic hypertrophy; and intravenously at 100 to 300 mg/kg for squamous ceU lung cancer.
- the combination of D-glutathione and ribavirin is preferably given for bacterial pneumonia (e.g., 100 mg - 1 g D-glutathione oraUy and 1-10 g ribavirin inhaled) and for metastatic breast cancer, metastatic testicular cancer and metastatic prostate cancer (e.g., 100 - 300 grams/kg D-glutathione intravenously up to four times or more a day and 1-10 g ribavirin intravenously).
- Treatment is continued as long as symptoms and/or pathology ameUorate.
- the inhibitor of glutathione-dependent formaldehyde dehydrogenase can be administered alone for the second embodiment or in combination with conventional therapy for the disorder being treated or in combination with newly discovered agents for use for therapy of the disorder treated and/or in combination with any other agent that imposes nitrosative or oxidative stress.
- Agents for selectively imposing nitrosative stress to inhibit proliferation of pathologicaUy proliferating ceUs in combination therapy with GS-FDH inhibitors herein and dosages and routes of administration therefor include those disclosed in U.S. Patent No. 6,057,367, the whole of which is incorporated herein.
- Supplemental agents for imposing oxidative stress i.e., agents that increase GSSG (oxidized glutathione) over GSH (glutathione) ratio or NAD(P) over NAD(P)H ratio or increase thiobarbituric acid derivatives
- GS-FDH inhibitors include, for example, L-butMo ne-S-siilfox-Lmine (BSO), glutathione reductase inhibitors (e.g., BCNU), inhibitors oruncouplers of mitochondrial respiration and drugs that increase reactive oxygen species (ROS), e.g., adriamycin, in standard dosages with standard routes of administration.
- BSO can be given intravenously or oraUy at 10-30 grams per' day.
- the patient has a disorder associated with a deficieucy in nitric oxide.
- disorder associated with a deficiency in nitric oxide is used herein mean disorder where NO deficiency is a feature and the deficiency constitutes less NO than the norm or less than the normal NO bioactive response.
- disorders associated with a deficiency in nitric oxide include atherosclerosis, restenosis, and disorders involving deficiency in NO in tissues where NO is necessary to keep the tissues aUve, e.g., deficiency in NO in endotheUal ceUs, hepatocytes and certain lung sites, including Uver diseases comprising inflammatory liver disorders, including, for example, chronic viral hepatitis B, chronic hepatitis C, alcohoUc Uver injury, drug (including acetaminophen)-induced Uver injury, primary biUary cirrhosis, autoimmune hepatitis, nonalcohoUc steatohepatitis and Uver transplant rejection.
- Uver diseases comprising inflammatory liver disorders, including, for example, chronic viral hepatitis B, chronic hepatitis C, alcohoUc Uver injury, drug (including acetaminophen)-induced Uver injury, primary biUary cirrhosis, autoimmune
- the NO deficiency can be detected in seru or in blood vessel responses.
- the NO deficiency is inherent in the injurious event which removes the source of NO.
- the NO deficiency is detected in Uver tissue.
- the inhibitors of glutathione-dependent formaldehyde dehydrogenase for the first subset of the third embodiment are those described above.
- therapeuticaUy effective amount for the first subset of the third embodiment means a glutathione-dependent formaldehyde dehydrogenase inhibiting amount in vivo that causes ameUoration of the disorder being treated or protects against risk associated with the disorder.
- a therapeuticaUy effective amount for treating atherosclerosis, a therapeuticaUy effective amount is a blood vessel dUating effective amount.
- a therapeuticaUy effective amount is a restenosis inhibiting effective amount.
- an effective amount is a Uver tissue inflammation ameUorating amount.
- the dosage for the first subset of the third embodiment i.e., the therapeuticaUy effective amount
- the patients include mammals including humans.
- the prefened routes of administration are oral and parenteral including intravenous with coating on an implanted stent being very appropriate for treating restenosis.
- a prefened agent for treating a patient with atherosclerosis is D-glutathione administered by oral route at a dqsage ranging from 0.5 to 100 mg/kg.
- a prefened agent for treating a patient having or at risk for restenosis is D- glutathione administered on a stent at a dosage ranging from 1 nanomole to 100 micro-moles.
- a prefened agent for treating Uver diseases is D-glutathione a-lministered by intravenous route of administration at a dosage ranging from 1 to 1,000 mg/kg.
- Treatment is continued for the first subset of the third embodiment as long as symptoms and or pathology ameUorate.
- the patient has a disorder where NO bioactivity is beneficiaUy increased for pharmacological effect.
- NO bioactivity is beneficiaUy increased for pharmacological effect.
- NO production may or may not be normal but in either case, pharmacological amounts are required to reverse the blood pressure increase, or in restenosis the blood vessel may heal with restoration of NO production, but more NO may be required to treat process (so no more smooth muscle proliferation).
- Another disorder that is embraced in the second subset of the third embodiment is heart faUure.
- StiU another disorder that is embraced in the second subset of the third embodiment is angina.
- the inhibitors of glutathione-dependent formaldehyde dehydrogenase for the second subset of the third embodiment are those described above.
- therapeuticaUy effective amount for the second subset of the third embodiment means a glutathione-dependent formaldehyde dehydrogenase inhibiting amount in vivo that causes ameUoration of the disorder being treated or protects against risk associated with the disorder.
- a therapeuticaUy effective amount for treating hypertension, a therapeuticaUy effective amount is a blood pressure lowering effective amount.
- a therapeuticaUy effective amount is a smooth muscle proliferation inhibiting amount.
- a therapeuticaUy effective amount is an apoptosis inhibiting effective amount.
- a therapeuticaUy effective amount is an angina ameUorating effective amount.
- the dosage for the second subset of the third embodiment ranges from 1 ⁇ g to 10 g/kg and often ranges from 10 ⁇ g to 1 g/kg or 10 ⁇ g to 100 mg/kg body weight of the patient, per day.
- the patients include mammals including human.
- the prefened routes of administration are oral and parenteral including intravenous with coating on an implanted stent being appropriate to inhibit smooth muscle proliferation after a bloodvessel is healed in respect to restenosis.
- prefened agents, dosages and routes of administration in connection with treating hypertension and inhibiting smooth muscle ceU proliferation are those described in conjunction with treating hypertension and restenosis vis-a-vis other embodiments herein as described above.
- Prefened agent for treating heart faUure or angina is D-glutathione administered oraUy at 0.5 to 100 mg/kg.
- Treatment is continued for the second subset of the third embodiment for as long as symptoms and/or pathology ameUorate.
- the inhibitor of glutathione-dependent formaldehyde dehydrogenase can be administered alone for the third embodiment or in combination with conventional therapy for the disorder being treated or in combination with newly discovered agents for use for therapy of the disorder treated and or in combination with any other agent that imposes nitrosative stress or which is functional for pharmacological deUvery of NO or NO related components for therapeutic appUcation or which upregulates endogenous NO.
- agents for imposing nitrosative stress for this case of the third embodiment and dosages and routes of administration therefor are those described for the second embodiment compatible with treatment of the disorders of the third embodiment.
- the agents functional for pharmacological delivery of NO or NO related compound have the moiety -RNO x where R is N, C, S, O or transition metal and x is 1 or 2.
- R is N, C, S, O or transition metal and x is 1 or 2.
- known agents e.g., nitroglyceiin or nitroprusside used in conventional amounts with conventional routes of administration.
- the agents for upregulating endogenous NO include cytokines, e.g., tumor necrosis factor alpha, interferon gamma and interleuken l ⁇ used in conventional amounts with conventional routes of administration, to activate or upregulate NO synthase to make NO, and substrates for NO synthase, e.g., L-arginine (e.g., in an amount of 2-10 grams, e.g., 6 grams per day administered systemicaUy).
- cytokines e.g., tumor necrosis factor alpha, interferon gamma and interleuken l ⁇ used in conventional amounts with conventional routes of administration, to activate or upregulate NO synthase to make NO
- substrates for NO synthase e.g., L-arginine (e.g., in an amount of 2-10 grams, e.g., 6 grams per day administered systemicaUy).
- nitrates i.e., nitroglycerin or nitroprusside standard of care respectively
- GS-FDH inhibitor e.g., 1 mM D-glutathione
- patients with angina can be treated with nitroglycerin administered in conventional amounts with conventional route of administration concomitantly with inhibitor of glutathione-dependent formaldehyde dehydrogenase, e.g., D-glutathione administered oraUy at 0.5 to 100 mg kg or any of the other GSD-FDH inhibitors specificaUy recited above.
- inhibitor of glutathione-dependent formaldehyde dehydrogenase e.g., D-glutathione administered oraUy at 0.5 to 100 mg kg or any of the other GSD-FDH inhibitors specificaUy recited above.
- patients with maUgnant hypertension from heart faUure treated with nitroprusside in conventional amounts with conventional route of administration can be concomitantly administered GS-FDH inhibitor, e.g., D-glutathione administered oraUy at 0.5 to 100 mg/kg or any of the other GS-FDH inhibitors specificaUy recited above.
- GS-FDH inhibitor e.g., D-glutathione administered oraUy at 0.5 to 100 mg/kg or any of the other GS-FDH inhibitors specificaUy recited above.
- the mechanism of the invention is shown by the foUowing background example and the invention is illustrated by the foUowing working examples.
- E- M values, K ⁇ values and K ⁇ K ⁇ values were obtained based on assays using 12 nM enzyme, 0.2 mM NADH and 10-500 ⁇ M GSNO using as buffers (100 mM; 0.1 mM DTPA), sodium acetate (pH 4 - 5), MES (pH 6), BisTrisPropane (pH 7) and Tris (pH 7.5 - 9).
- the experiment showed a GSNO-con-iuming activity in E. coli lysates that was dependent on NADH.
- the GSNO metabolizing activity fromE. coli strain RK4936 was purified from 8 Uters of stationary phase ceUs. A, 100,000 g supernatant in 20 mM BisTrisPropane (pH 7) was appUed to a 5X40 cm Q-Sepharose column and eluted with a linear NaCl gradient in 20 mM BisTrisPropane (pH 7). Active fractions were pooled, adjusted to 1 M (NH 4 ) 2 SO 4 , and appUed to a 2.5 x 20 cm column of Butyl Sepharose. ⁇ lution was done with a decreasing (NH 4 ) 2 SO 4 gradient from 1 to 0 M.
- the enzyme was further purified on a MonoQ column. Active fractions were appUed to a 1.6 x 10 cm column of AMP Sepharose, washed with 0.15 M NaCl, and eluted with 20 mM NAD + . The protein was pure as judged by SDS- PAG ⁇ (yield: 0.52 mg). Limited N-terminal sequencing after blotting onto a PNDF membrane identified the protein as the glutathione-dependent formaldehyde dehydrogenase.
- Rates of nitrosothiol accumulation in the medium of RAW 264.7 ceUs was found to be very slow at the limits of detection, and this result was consistent with what was found in Kosower, N. S., et al., Int. Rev. Cytol. 54, 109 (1978).
- GSNO was incubated in reaction buffer supplemented with NADH or in ceU lysates with and without NAD.
- CeUs were homogenized by sonication in a solution containing 20 mM Tris-HCl (pH 8.0), 0.5 mM EDTA, 0.1% NP-40 and 1 mM phenylmethylsulfonyl (PMSF).
- PMSF phenylmethylsulfonyl
- 0.86 mg/ml RAW 264.7 lysate was incubated with 100 ⁇ M GSNO in reaction buffer (20 M Tris-HCl (pH 8.0), 0.5 mM EDTA) with 0 or 200 ⁇ M NADH at room temperature for various times.
- Nitrosothiol levels in the reaction mixture were measmed by the Saville assay as described in Stamler, J. S., Science 276, 2034 (1997).
- GSNO-dependent NADH consumption was also measmed using either absorbance (OD 340 nm) or fluorescence (340/455 nM) measmements of NADH.
- the results showed that GSNO was quickly metabolized when it was incubated with extracts from resting macrophages.
- the same result of GSNO being quickly metabolized was obtained from cytokine activated macrophages.
- the GSNO metabolizing activity required NADH and was ineffective at metabolizing alternate nitrosothiols.
- GSNO-metaboUzing activity of RAW 264.7 ceUs was recovered in a single function foUowing anion exchange on a MonoQ column. Further purification over a 5' AMP Sepharose column yielded a single band of about 43 kDa in a sUver-stained SDS-PAGE gel.
- the ceU lysate was first subjected to stepwise ammonium sulfate precipitation. The GSNO reductase activity was precipitated between 45-75% ammonium sulfate. After dialysis against 20 mM Tris-HCl (pH 8.0), the proteins were fractionated on a MonoQ column with increasing concentrations of NaCl.
- the GSNO reductase activity was finaUy purified with a 5' AMP Sepharose 4B affinity column (Amershem Pharmacia) in 20 mM phosphate buffer. SDS-PAGE and Coomassie blue staining gave the single band of about 43 kDa.
- the purified protein was digested by trypsin and the resulting peptides were analyzed by mass spectrometry.
- Peptide mass database search with GPMAW program identified the protein as mouse GS-FDH(SP-P28474) with high scores, matching 8 fragments (42% coverage) to mouse GS-FDH.
- the purified protein also oxidized the formaldehyde-glutathione adduct, S-hydroxymethylglutathione, previously thought to be the major enzyme substrate.
- the specific activity for this oxidation was only about 6% of the GSNO reducing activity.
- GSNO is the prefened substrate of this enzyme.
- GSNO reductase activity of mouse macrophage ceUs is remarkably high and specific toward GSNO, and this activity constitutes a major metaboUc pathway for GSNO in mouse macrophages.
- the data indicates that by eliminating endogenous GSNO, GS-FDH protects from nitrosative stress.
- mice SVEC4-10 endotheUal ceUs (ceU line obtained from the ATCC) and mouse SV40LT-SMC smooth muscle ceUs (ceU line obtained from the ATCC).
- GSNO (200 ⁇ M) was incubated with 0 or 4 ⁇ g/ml of the ceU lysates in reaction buffer (20 mM Tris-HCl (pH 8.0), 0.5 mM EDTA) supplemented with NADPH (300 ⁇ M), NADPH (300 ⁇ M), glutathione (GSH, 2 mM), and ascorbic acid (ASA, 500 ⁇ M) in combinations as set forth in the table below, at 37 °C for 5 minutes.
- reaction buffer (20 mM Tris-HCl (pH 8.0), 0.5 mM EDTA) supplemented with NADPH (300 ⁇ M), NADPH (300 ⁇ M), glutathione (GSH, 2 mM), and ascorbic acid (ASA, 500 ⁇ M) in combinations as set forth in the table below, at 37 °C for 5 minutes.
- GSNO metabolizing activity is shown as percent of that in the starting material and ASA is ascorbate and GSH is glutathione (ascorbate and glutathione are redox co-factors that have been proposed as decomposing GSNO).
- yeasts are often used to identify and characterize mammaUan genes. See Cardenas, M. E., et al., Clin. Microbiol. Rev. 12, 583 (1999).
- yeast strain Y190 ceUs (Clontech; Genbank Accession No. Z74216) were tested for GSNO reductase activity.
- GSNO was incubated in buffer or lysate of the yeast ceUs.
- the test shows the yeast strain Y190 ceUs have robust GSNO reductase activity.
- the mutant ceUs were no more sensitive to the toxic effects of EL J O J than wUd-type Y190 ceUs.
- Hepatocytes of wUd-type mice and their GS-FDH "7" Uttermates were harvested after perfusion of the livers with Liberase (Roche), and purified by repeated differential sedimentation at 50x g, foUowed by centrifugation over a 30% PercoU solution. Hepatocytes (over 95% viabiUty by trypan blue exclusion) were plated at a density of 2 x 10 4 ceUs/cm 2 in gelatin-coated flasks, and incubated for 24 horns.
- ceUs were then cultured in the presence of recombinant mouse tumor necrosis factor- (500 units/ml), interferon-garnma (100 units/ml), interleuken - l ⁇ (200 units/ml) and lypopolysaccharide (LPS, 10 ⁇ g/ml; E. coli 0128:B12; Sigma) for 14 and 40 hours.
- Nitrosylation levels in hepatocytes were measured as described in Eu, J., et al., Biochemistry 39, 1040-1047 (2000). Data showed total nitrosothiol but not alternative NO complexes, were approximately 50% higher in ceUs deficient in GS-FDH and that the majority of nitrosothiol was bound to protein.
- Liver tissues from wild-type and GS-FDH-deficient mice were homogenized in an enzyme reaction buffer (phosphate-buffered saline, GIBCO 14190-144, supplemented with 0.1% NP-40 and 1 mM PMSF).
- enzyme reaction buffer phosphate-buffered saline, GIBCO 14190-144, supplemented with 0.1% NP-40 and 1 mM PMSF.
- GSNO (200 ⁇ M) was incubated with 0 or 3 ⁇ g/ ⁇ l of the liver homogenate in buffer supplemented with NADH (300 ⁇ M), buffer supplemented with NADPH (300 ⁇ M), buffer supplemented with glutathione (2 M), buffer supplemented with ascorbic acid (500 ⁇ M) or buffer supplemented with NADPH (300 ⁇ M), glutathione (2 mM), and ascorbic acid (500 ⁇ M), at 37 °C for 5 minutes.
- Example I A 25-year-old white female presents to the Emergency Room wheezing with an FENl of 1 Uter. She is given an intravenous infusion of D-glutathione 50 mg/kg Q.6 hours and her breathing improves. She is subsequently given inhaled D-glutathione (nebulized solution of 10 mM D-glutathione in 3 cc of normal saline) to be taken twice daUy.
- Example II A 17-year-old male with cystic fibrosis presents to the Emergency Room with difficulty breathing and a fever. He is given an inhaled treatment of S-nitrosoglutathione (10 mM in 3 cc normal saline) in combination with D-glutathione (3 mM in 10 cc normal saline). His symptoms resolve over the foUowing day.
- S-nitrosoglutathione (10 mM in 3 cc normal saline)
- D-glutathione 3 mM in 10 cc normal saline
- Example IN A 70-year-old male status post CABG x 2 presents with unstable angina. He is treated with betablockers and nitrates but continues to experience chest pain. An intravenous infusion of 100 mg per kg D-glutathione is given Q6 hours with reUef of his symptoms. This is an example of treating heart disease.
- Example N A 60-year-old white male presents to his primary care physician. On routine physical exam his blood pressure is 160/90. The patient is begun on 600 miUigrams of D- glutathione BID. On foUow-up examination three weeks later, his blood pressure is 140/80.
- Example NI The heart disease treated in Example IN is ischemic coronary syndrome, so Example IN is also an example of treating ischemic coronary syndrome.
- Example N ⁇ A 60-year-old white male who undergoes cardiac catheterization and an acetylcholine infusion, shows impaired relaxation (earUest marker of atherosclerosis). The patient is treated with D-glutathione, 600 mg TED for a week. Upon retesting, the patient shows an improved response to acetylcholine.
- Example NHI A 65-year-old male with intractable angina is administered ribavirin as 6 grams diluted to a final volume of 300 cc in sterile water and injected at a final concentration of 20 miUigrams per milliliter, given, daUy for seven days. The patient's angina had improved by six weeks. This is an example of treating disease characterized by angiogenesis.
- Example DC A 43-year-old female presents with shortness of breath and hemoptysis.
- a NQ scan shows a pulmonary emboUsm and the patient is begun on inhaled ribavirin, 6 grams diluted in 300 cc and administered by a smaU particle aerosol generator. Treatment is ca ⁇ ied out for 12 hours/day for three days. The patient shows improvement in symptoms. This is an example of treating a disorder where there is risk of thrombosis occun ⁇ ng.
- a 72-year-old white male presents with chest pain seven days post-angioplasty and cardiac catheterization reveals restenosis.
- a ⁇ ir stent coated with mycophenoUc acid (drug concentration of 30% per polymer) was deployed with successful results. The patient was discharged the foUowing day, and did weU.
- a 17-year-old male with chronic psoriasis presents at the dermatologist.
- a paste comprised of acetylsaUcyUc acid, 2%, combined with 5% ribavirin was appUed topicaUy for 8 hours a day. This was repeated daUy for two weeks at which time the psoriatic lesion had resolved. This is an example of treating a patient with a chronic inflammatory disease.
- Example XII A 15-year-old boy presents to the Emergency Room having ingested a toxic dose of Tylenol. Liver function tests are elevated. The doctor infuses D-glutathione at 200 milligrams per kUogram every 6 horns with gradual normalization of liver function over the foUowing week. This is an example of treating a patient for a disease where there is risk of apoptosis occurring.
- Example Xi ⁇ A 70-year-old diabetic with a history of impotence presents to his urologist. He is treated with Viagra but shows no improvement. His physician adds topical mycophenoUc acid (5% paste) with good results.
- Example XIV A 40-year-old alcohoUc male presents with swoUen abdomen and elevated LSTs. The patient is infused with D-glutathione at 200 milligrams per kilogram every 6 horns for two weeks. The swelling and elevated LSTs are reduced.
- Example XV A 52-year-old female presents with pneumonia to the Emergency Room. A sputum cultme grows out pseudomonas resistant to antibiotics and she is given D-glutathione, 600 rniUigrams TED, and inhaled ribavirin 6 gm daUy for ten days with a resolution of pneumonia.
- Example XVI A 9-year-old presents to her pediatrician who diagnosis ringworm She appUes topical ointment comprised of 5% ribavirin acid daUy for a week and the skin lesion resolve.
- Example XN ⁇ A 52-year-old female status post lung transplant is admitted to the hospital with viral pneumonia. She is given inhaled D-glutathione, 3 mM/3 cc normal saline four times a day with resolution of symptoms of cough and shortness of breath.
- Example XVDI A tape test done by a pediatrician confirms the suspected diagnosis of pinworm. The cMld is given 1 gram of D-glutathione daUy for three days and the signs and symptom resolve.
- Example XIX A routine chest X-ray shows the presence of a right upper lobe lung mass in a 55- year-old smoker. Bronchoscopy shows a mass at the take off to the right upper lobe and a biopsy confirms diagnosis of squainous ceU cancer. A further work-up shows the patient to be stage 3B. The patient is treated with a regimen including three weeks of D-glutathione intravenously 200 milUgrams per Uogram four times a day for two weeks. On restaging, the patient is 3 A and thus a candidate for surgery.
- Example XX A 25-year-old has a biopsy done on an axUlary node which estabUshes the diagnosis of Hodgkins disease. The patient is given 1 gram of D-glutathione three times a day for a month with resolution of adenopathy.
- Example XXI A 55-year-old female with metastatic breast cancer, umesponsive to conventional measmes, is begun on combination of intravenous ribavirin 6 grams a day for seven days and intravenous D-glutathione, 200 grams per kUogram QED. Symptoms of bone pain in her back resolve after two days.
- Example XXII A 30-year-old white male presents with a testicular mass and metastasis to lung and brain. The diagnosis is metastatic testicular cancer. The patient unresponsive to conventional measures, is begun on combination of intravenous ribavirin 6 grams a day for seven days and intravenous D-glutathione, 200 grams per kUogram QED. Symptom of headache resolve after two days.
- Example XXm A 65-year-old male presents with highly elevated PSA and metastasis to bone.
- the diagnosis is metastatic prostate cancer.
- the prostate cancer is treated with conventional therapy.
- the metastasis to bone is umesponsive to conventional measmes.
- the patient is begun on combination of intravenous ribavirin 6 grams a day for seven days and intravenous D-glutathione, 200 grams per kUogram QED. Symptoms of bone pain in back resolve after two days.
- Example XXIV A 65-year-old male has a stent placed for 90% lesion of the left anterior descending coronary artery. He is sent home on a regimen including D-glutathione, 600 mg P.O. three times a day for a month and does weU.
- Example XXV A 55-year-old male complaining of urinary frequency and hesitancy (diagnosis: benign prostatic hypertrophy) is begun on D-glutathione, 600 mg three times a day. His symptoms graduaUy resolve over the foUowing three months.
- Example XXVI A 27-year-old female with acute viral myocarditis develops severe heart faUure. Her EF is 10%, and she is unresponsive to conventional therapy. She is placed on the transplant list. Infusion of D-glutathione, 1 gram TED for 10 days, stabilized her deteriorating course.
- Example XXNH A 60-year-old male presenting with angina is treated with nitroglycerine (0.6 mg subUnguaUy) and responds only partly as evidenced by persistent chest pain. The patient is concomitantly started on D-glutathione, 600 mg TDD, with total reUef of symptoms.
- the other GS-FDH inhibitors specificaUy recited above can be substituted for D-glutathione in appropriate amounts with similar results.
- Example XXVm A 65-year-old male presents with heart faUure and malignant hypertension. Blood pressure is reduced from 240 to 200 systoUc with mtroprusside (1.0 ⁇ g/kg/min IV infusion, for 10 minutes) and is reduced further to 160 by coadministration of GS-FDH inhibitor, e.g., D-glutathione, 600 mg, TED. Variations
Abstract
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US09/757,610 US7179791B2 (en) | 2001-01-11 | 2001-01-11 | Inhibiting GS-FDH to modulate NO bioactivity |
PCT/US2001/044709 WO2002055018A2 (en) | 2001-01-11 | 2001-12-14 | Inhibiting gs-fdh to modulate no bioactivity |
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-
2012
- 2012-06-08 US US13/491,752 patent/US20120245116A1/en not_active Abandoned
-
2014
- 2014-04-24 US US14/260,906 patent/US20140235528A1/en not_active Abandoned
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Also Published As
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EP1349562B1 (en) | 2011-05-25 |
US7615535B2 (en) | 2009-11-10 |
WO2002055018A3 (en) | 2002-09-06 |
US20070111949A1 (en) | 2007-05-17 |
ATE510551T1 (en) | 2011-06-15 |
US20020128205A1 (en) | 2002-09-12 |
US20100015121A1 (en) | 2010-01-21 |
US20120245116A1 (en) | 2012-09-27 |
AU2002239387A1 (en) | 2002-07-24 |
EP1349562A4 (en) | 2008-08-06 |
US8217006B2 (en) | 2012-07-10 |
US7179791B2 (en) | 2007-02-20 |
WO2002055018A2 (en) | 2002-07-18 |
US20140235528A1 (en) | 2014-08-21 |
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